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Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5

ABSTRACT: Adaptor proteins often serve as hubs to regulate diverse protein complexes in cells. This multitude of functions can complicate the study of adaptors, as their genetic disruption typically impairs the activities of all parent complexes (or ‘complexoforms’). Here we describe the chemical proteomic analysis of bicyclopyrrolidine acrylamide stereoprobes in human cells, leading to the discovery of a ligand – FWG-33B – that stereoselectively reacts with cysteine-100 (C100) of the methyltransferase (MT) adaptor TRMT112. FWG-33B showed negligible reactivity with uncomplexed recombinant TRMT112, and this interaction was restored exclusively in the presence of METTL5, but not other MT partners of TRMT112. A co-crystal structure revealed that FWG-33B binds at a composite pocket proximal to C100 that is templated by METTL5 and absent in other TRMT112:MT complexes. Subtle structural rearrangements promoted by FWG-33B in turn lead to allosteric agonism of METTL5, thus revealing how covalent ligands targeting a pleiotropic adaptor can confer partner-specific functional effects through reactivity with a single complexoform.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Friedrich Wieland Goetzke

LAB HEAD: Benjamin Cravatt

PROVIDER: PXD063358 | Pride | 2026-01-08

REPOSITORIES: Pride

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			Action	DRS
	20220714_Ramos_FWG34_FWG_enrich_01.raw	Raw
	20220714_Ramos_FWG34_FWG_enrich_02.raw	Raw
	20220714_Ramos_FWG34_FWG_enrich_03.raw	Raw
	20220714_Ramos_FWG34_FWG_enrich_04.raw	Raw
	20220714_Ramos_FWG34_FWG_enrich_05.raw	Raw

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